Microbial infection is a major public health threat that can be associated with high mortality, and that can also often amplify and lead to chronic inflammation, also resulting in serious complications. The current emergence of multi-drug resistant strains adds to the threat of infections. These features are especially evident in compromised patients in whom drug-resistant microbial pathogens infect with high mortality and morbidity. During infection, microbes exploit a variety of host components to promote their pathogenesis. Among these, cell surface heparan sulfate proteoglycans (HSPGs) are targeted by a wide spectrum of microbes. Cell surface HSPGs function as selective regulators of various molecular interactions, including those important to microbial pathogenesis and host defense. These HSPGS not only function at the cell surface, but also in the extracellular environment as soluble HSPGS because they can be shed as intact ectodomains in response to tissue injury, including those caused by infections. The long term objective of this research is to delineate how cell surface HSPGs regulate, in part, the highly complex host response to microbial infections. This proposal focuses on the role of syndecan-1, the predominant cell surface HSPG of epithelia. The goal of this application is to elucidate the molecular mechanisms that are responsible for exploitation of syndecan-1 shedding by bacterial pathogens to enhance their lung virulence. Three inter-related hypotheses will be tested in three aims: Specific Aim 1. Binding of certain virulence factors to their host receptors triggers signaling events that lead to activation of syndecan-1 shedding will be assessed by determining in molecular detail how LasA, a virulence factor for Pseudomonas aeruginosa lung infection, activates syndecan-1 shedding; Specific Aim 2. Syndecan-1 ectodomains regulate the host response by inhibiting innate defense mechanisms will be evaluated by establishing whether syndecan-1 ectodomains, via their specific structural features in their HS chains, inhibit the activity of cytokines and antimicrobials to enhance bacterial virulence in the lung; and Specific Aim 3. This mechanism is used by several major pulmonary bacterial pathogens will be probed by evaluating whether Staphylococcus aureus exploits syndecan-1 shedding to enhance its lung virulence. These studies, which delineate how cell surface HSPGs such as syndecan-1 are exploited by microbes for their pathogenesis, should provide a foundation for the development of novel prophylactic and therapeutic agents to combat infections caused by major opportunistic bacterial pathogens.